Nucleophilic substitution approach to 4′-substituted thymidines by employing 4′-benzenesulfonyl leaving group

Synthesis of 4′-substituted thymidines was investigated based on nucleophilic substitution using organosilicon and organoaluminum reagents. Two substrates having a benzenesulfonyl leaving group at the 4′-position were prepared for this purpose: 1-[4-benzenesulfonyl-3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-α-l-threo-pentofuranosyl]thymine (8α) and the 4′-(benzenesulfonyl)thymidine derivative (8β). The reaction of 8α with organosilicon reagents (Me3SiCH2CHCH2 and Me3SiN3) in combination with SnCl4 gave preferentially the 4′-substituted β-d-isomer: the 4′-allyl (12β) and 4′-azido (15β) derivatives, respectively. The reaction of 8α with AlMe3, however, gave the 4′-methyl-α-l-isomer (16α) as the major product, presumably through an ion pair mechanism. By employing the substrate 8β in this reaction, the 4′-methylthymidine derivative (16β) was obtained exclusively in high yield. The 4′-ethyl (20β) and 4′-cyano (24β) derivatives were also synthesized by reacting 8β with the respective organoaluminum reagent.